Cryptococcus gattii (Cg) was considered to be a fungal pathogen restricted to tropical and subtropical climates until 1999, when an outbreak caused by a previously unrecognized, hypervirulent strain of a new molecular group (VGIIa) became evident on Vancouver Island (VI), Canada. During the years spanning 1999-2003, the VI incidence of Cg infection in humans exceeded that of historically endemic regions. Since 2004, this outbreak has spread to mainland Canada and to multiple states in the Pacific Northwest U.S. Also, other VG group isolates have caused disease in other non-contiguous states in the U.S., including Hawaii, New Mexico, Rhode Island, Michigan, and Georgia. Mortality rates have exceeded 30%, largely associated with delayed diagnosis and neurologic morbidity. Recognition of this pathogen is important, as preliminary studies suggest variability in antifungal susceptibilities as well as the need for a different clinical approach, given excessive neurologic inflammation associated with central nervous system infection. A large proportion (50%) of patients have no underlying immunosuppressive risk, but early studies suggest that the infection serves as a sentinel for unsuspected adult-acquired immunodeficiency, including deficiencies in specific IgG subtypes and the presence of auto-antibodies to granulocyte macrophage colony stimulating factor (GM CSF). The goal of this proposal is to perform a prospective cohort study that will increase our understanding of this emerging infection. Focus is placed on defining host risks, appropriate management of neurologic complications, and effective antifungal therapies. In Aim 1, we will perform a prospective cohort study, employing an internet-based case report form in an established network of sites led by the global Mycoses Study Group, with site identification facilitated by national and state public health officials. Daa and samples obtained as part of the prospective cohort study will enable sub-studies to evaluate new diagnostics. In Aim 2 a nested case-control study will be performed to evaluate the immunologic correlates of Cg infection and progressive disease in people who are without apparent immunosuppressive conditions. This aim is enabled by detailed studies performed by intramural investigators at the NIH clinical center. This study represents our first concerted effot to describe clinical features of this important emerging outbreak in the U.S. Our long-term goal is to generate the information needed to effectively prevent and treat this infection.